JP2018523551A - Autoimmune mechanical immune regulation - Google Patents

Abstract

A method is disclosed that includes drawing arterial blood from a patient into an extracorporeal circuit and performing apheresis on the blood to remove one or more components from the blood. The method further includes the step of returning the blood to which the component / replacement solution has been added to the patient in a pulsatile flow.
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Description

  The present invention relates to mechanical immune regulation of autoimmunity.

  Apheresis is the process by which a donor or patient's blood passes through a device that separates one or more components and returns the remainder to the patient. This is therefore an extracorporeal therapy. Therapeutic apheresis can be performed utilizing the peripheral venous system to replace 3 liters of plasma with 3 liters of albumin solution. Patients are typically given 5-15 therapeutic apheresis sessions based on estimates from the patient's historical data to suppress symptomatic disease. Patients are treated for many years in this way because the actual immune disease process has not been effectively treated.

  Conventional plasma exchange methods are performed using the peripheral vascular system of the venous tract. Only immune factors floating in the bloodstream are removed, and the concentration and movement of immune factors within the secondary lymphatic system are unchanged. Thus, the signal pathway of the patient's immunological disease process remains unchanged and the patient's underlying immunological disease process remains unchanged.

  Many attempts have been made to improve the effectiveness of therapeutic apheresis, but to date, nothing effectively changes immune factor migration. The movement of immune factors relative to other immune factors in the body's tissues, blood vessels, and lymphatic system affects the function of the entire immune system. Traditional therapeutic apheresis is of a degree that provides only symptomatic relief without treatment of the disease process.

  The present disclosure relates generally to therapeutic apheresis systems, and more specifically to methods and apparatus for performing therapeutic apheresis. In one embodiment, the present disclosure provides a highly efficient form of therapeutic apheresis that modulates the immune system, thereby treating one or more immunological disease processes.

  The therapeutic apheresis according to one embodiment of the present disclosure is to return at least a portion of the blood from the extracorporeal circuit to the patient in a pulsatile flow. In other embodiments, the disclosed methods and systems utilize the central arterial system to exchange plasma volume and immunomodulate disease processes. The present disclosure is based in part on utilizing the proven concept of cardiovascular and combining the concept of intermittent and continuous flow therapeutic apheresis. One advantage of the therapeutic apheresis of the present disclosure is that it reduces the time that the patient spends in a therapeutic apheresis session over the lifetime of the patient, not just during the initial treatment process. The term “patient” is broadly defined herein to include both humans and animals.

  All disease states with immune processes that currently use conventional therapeutic apheresis can benefit from the therapeutic apheresis system described herein. In addition, immunoregulation such as multi-organ transplantation (including immunosuppression / rejection and induction / desensitization), general infection, allergies, need for vaccine work such as inverse vaccine, and cancer status. Other immunological disease processes that improve may benefit from the therapeutic apheresis system described herein.

  By improving the effectiveness of this form of apheresis, it can be used in pathological conditions where it is beneficial to avoid immune complex injury (eg inflammation) and / or to suppress the accumulation of immune factors / inflammatory. The therapeutic apheresis of the present disclosure can prevent consequential damage caused by such a condition, such as in a cardiac condition where an immune pathology occurs.

  The features and advantages of the present disclosure will be readily apparent to those of ordinary skill in the art upon reading the following description of the embodiments.

  The patent or application file contains at least one drawing made in color. Copies of this patent or patent publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

  Some specific exemplary embodiments of the present disclosure can be understood by partially referring to the following description and the accompanying drawings.

FIG. 1 is a schematic diagram according to an embodiment of the present disclosure. FIG. 2 is a schematic diagram showing further details of a part of the schematic diagram of FIG. FIG. 3 is a schematic diagram showing a part of the human venous system and arterial system.

  While the disclosure is susceptible to various modifications and alternative forms, specific exemplary embodiments are shown in the drawings and are described in greater detail herein. However, the description of certain exemplary embodiments is not intended to limit the invention to the precise form disclosed, but rather, the disclosure is to some extent set forth in the appended claims. Including all variants and equivalents.

  The present disclosure relates generally to therapeutic apheresis systems, and more specifically to methods and apparatus for performing therapeutic apheresis. The systems and methods of the present disclosure provide a highly efficient form of therapeutic apheresis that modulates the immune system, thereby treating one or more immunological disease processes. The therapeutic apheresis of the present disclosure is based at least in part on returning blood to the patient in a pulsatile flow. As used herein, the term “blood” refers to whole blood or any replacement component of whole blood.

  The methods and systems of the present disclosure increase the rate and pulsatility of arterial perfusion. At the same time, immune factors are removed from the arterial blood plasma and blood depleted of immune factors is returned to the patient upstream of the central arterial system. This blood is returned to the capillary level lymphatic system at an increased rate and pulse. The mechanism of protein transvascular flow, which is plasma protein translocation, results from a decrease in plasma protein concentration that causes increased lymph flow, which is greater than the permeability of transvascular proteins. As a result, more immune factors migrate from the extravascular space to the intravascular space. Once the immune factor enters the intravascular space, it can be removed by the continuous plasma exchange process of the present disclosure.

  Overall, the disclosed methods and systems can “reset” fluid regulation pathways by removing immune factors from arterial flow and mechanically increasing hemodynamics of arterial flow. Humoral immunity changes when the flow and concentration of immune factors in the secondary lymphatic system involved in the patient's current disease process signaling pathway is removed. The body takes a natural way of travel to return to standard fluid regulation outside the blood vessels.

  The present disclosure generally uses an extracorporeal circuit configured to ingest arterial blood from a patient, performs apheresis on the blood to remove one or more components from the blood, and beats at least a portion of the blood from the extracorporeal circuit. It is directed to a method and system for kinetic return. As used herein, “pulsatile flow” refers to flow with periodic speed changes (eg, changes in pump operating speed). Such methods and systems can be used, inter alia, to produce an immunomodulatory effect in the patient's immune system. The term “immunomodulation” (and its derivatives) is used herein to refer to any therapeutic intervention (eg, patient's intervention) aimed at any modulation of the immune response to a desired level, as well as alteration of the immune system. Broadly defined to include (by inducing, enhancing, suppressing and / or increasing the immune system). In certain embodiments, the therapeutic apheresis of the present disclosure can be combined with radical therapy treatments such as immunosuppressants or other therapeutic agents suitable for their use or treatment of patients.

  The extracorporeal circuit is operatively connected to the patient's circulatory system. A catheter can be inserted into the patient via the subclavian artery for central arterial access to the aorta. Alternatively, a catheter can be inserted into the femoral artery, which is the route to the aorta. Catheter arterial access can be guided radiologically and may follow standard arterial catheter access for vascular procedures. Similarly, depending on the pathological condition requiring treatment, a catheter can be inserted into one or more major anatomical branches in the central arterial system instead of the aorta. Depending on pathological conditions such as neurological and / or orthopedic conditions that benefit from this form of apheresis, create different rates of return blood flow at various major anatomical branches across the central arterial system be able to.

  The extracorporeal circuit of the present disclosure includes an automated blood cell separator. Automatic blood cell separators can be used to balance fluids and maintain normal plasma volume. For apheresis, continuous flow centrifugation or intermittent flow centrifugation can be used. In some embodiments, the extracorporeal circuit includes an apheresis centrifuge.

  In certain embodiments, the pulsatile flow from the extracorporeal circuit is obtained by force from one or more pumps. In other embodiments, the pulsatile flow from the extracorporeal circuit is obtained by electrical stimulation to the heart to enhance the pulse wave from the heart. In such an embodiment, blood can be returned to the patient at a substantially constant rate while still having the desired pulsatile flow characteristics.

  The extracorporeal circuit of the present disclosure includes one or more pumps. Generally, the pump can return at least a portion of the blood from the extracorporeal circuit to the patient. In certain embodiments, the pump can also return a portion of the blood in a pulsatile flow. Suitable pumps include positive displacement pumps, roller pumps, ventricular pumps, piston pumps, kinetic pumps, centrifugal pumps, forced vortex pumps, magnetic pumps. In one embodiment, the pump can be placed in an indwelling catheter. In certain embodiments, the pump may have an output that approximates the left ventricular contractile flow output. In certain embodiments, the pump can have varying volume, timing, and fill / discharge ratio control. Pumping blood at a rate of about 0.1 liter / minute to 1.5 liter / minute, 0.5 liter / minute to 1 liter / minute, and 0.3 liter / minute to 0.6 liter / minute As can be seen, the pump can be configured to operate within a variable range. In one embodiment, the one or more pumps are located outside or near the end of an indwelling catheter that is placed in the patient's aorta or central artery bifurcation and configured to deliver axial flow. Can be done.

  The pump is operably connected to the controller. The controller is configured to generate one or more signals to the pump, and each pump is configured to operate according to information contained in each signal received from the controller. The controller controls the pump and provides a pulsatile flow of the portion of blood that is returned from the extracorporeal circuit to the patient. In certain embodiments, the controller adjusts the volumetric flow rate of the pump to coincide with the onset of ventricular contraction. The controller can also receive input regarding the patient's unique electrocardiogram or paced rhythm. The controller can also provide information to one or more pumps to return blood to the patient via the arterial system. The controller can also be configured to sense various patient pressures (eg, blood pressure) and decrease or increase pump speed to compensate if necessary. The controller may also be configured to sense other physiological parameters, such as bioimpedance, body movement and / or cardiac performance parameters, and adjust pump speed to optimize blood flow to the patient. it can. The controller may also be operably connected to other components of the system of the present disclosure. For example, the controller may be configured to generate and / or receive signals from an automated blood cell separator, temperature sensor, pressure sensor, air embolization sensor, pulse sensor (eg, ECG) and / or heat exchanger. . A standard power supply can be used in conjunction with the controller to provide the appropriate wattage that allows the system and / or method to operate.

  In one embodiment, one or more signals from the controller may cause one or more pumps to pulse blood flow to the patient. More particularly, the one or more pumps can have the ability to pump pulsatile blood flow to the patient such that the pulsatile blood flow returns to the patient in axial flow. The controller can change the pump speed either in sync with the heart rhythm or paced rhythm, or not in sync with the heart rhythm. In other words, the beat can mimic the rhythm of the patient's heart. Attempts to replicate blood flow to the patient at the patient's heart rate or at the target heart rate are believed to increase the effectiveness of the treatment. By way of illustration and not limitation, in mathematical and physical models, at the same average pressure, pulsatile blood flow has an energy content approximately 2.4 times that of non-pulsatile flow, thereby significantly increasing energy throughout the tissue. Was shown to dissipate. The pulsation directly affects the blood flow in the lymphatic system, and energy from the pulsatile flow in the capillaries and tissues is exchanged for the action that occurs on the material from the tissue to the lymphatic system. In certain embodiments, the controller is configured such that onset of pumping occurs less than about 75 milliseconds or about 75 milliseconds after the start of contraction as measured by an ECG trace. The controller can also include a programmed delay to allow the start of draining to be tuned to the delivered ECG signal.

  In one embodiment, the controller is configured to receive information about blood temperature and to control the heat exchanger. Such a heat exchanger can be used to regulate the temperature of the blood returned to the patient. The controller, along with the heat exchanger, changes the returned blood temperature at a normal range temperature or by increasing the temperature, consistent with the current body. The heat exchanger can be used to ensure that the blood temperature returned to the patient is at a suitable or acceptable temperature to reduce afterload resistance.

  In certain embodiments, the controller is also a pulse generator configured to generate one or more pacing signals (eg, electrical stimuli) to the heart to enhance the blood pulse wave returned to the patient. Is also included. In such embodiments, the controller may be operably connected to one or more leads disposed on or in the heart and disposed distal to the end of the indwelling catheter. The controller receives a sensing signal from the lead (eg, an ECG event), and a pulse generator within the controller is configured to generate one or more pacing signals to the lead based on the sensing signal. In such a configuration, the pulsatile flow of blood returning from the extracorporeal circuit to the patient is acted upon without mechanical pump pulsatile flow and still stimulates lymphatic circulation in the patient's secondary lymphatic system.

  In one embodiment, the velocity amplitude of the blood flow returned to the patient can be altered (eg, increased and / or decreased) from baseline while maintaining, increasing or decreasing the baseline pulse frequency. In this way, different velocities can be obtained in the return blood flow in order to cause changes in the movement of components that act on immune regulation.

  The systems and methods of the present disclosure may also include one or more pressure sensors, thermal sensors, pulse sensors (eg, electrocardiography (EKG) equipment), or any combination thereof. One or more heat exchangers can also be used. A suitable heat exchanger is one that can heat at least a portion of the blood to 5 degrees Fahrenheit beyond the normal body temperature range. In certain embodiments, a reservoir system can be used to facilitate the processing of blood and resulting components for plasma exchange. In addition, a controller and / or monitor board may receive one or more patient input information, such as blood characteristics, and track and / or display some blood characteristics of the blood returned to the patient.

  In one embodiment, the controller is configured to calculate a desired characteristic of blood returned to the patient via an algorithm. The purpose of the algorithm is to evaluate enhancements, changes or changes in the desired blood properties. This algorithm can be modified according to patient needs or plasma exchange characteristics based on, for example, the patient's physiological profile and / or disease. Plasma exchange properties are related to blood properties with respect to pulsatility, flow rate and / or temperature.

  Tubes or catheters used in the systems and / or methods of the present disclosure for moving blood or other fluids can be made of any suitable biocompatible or biomaterial. For example, plastic materials such as those that have the necessary strength and biocompatibility properties and that allow for directional flow capability can be used. Rigid biomaterials or flexible biomaterials may alternatively or additionally be utilized in the configuration. Examples of suitable tubing materials include those commonly used for extracorporeal circulation, such as apheresis, hemodialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO).

  In one embodiment, the system and method of the present disclosure uses a tube material having a low dielectric constant, a low coefficient of friction, non-reactivity, or a combination thereof. Examples of suitable tube materials include polytetrafluoroethylene (PTFE) and perfluoroalkoxy (PFA).

  As described above, the systems and methods of the present disclosure include an extracorporeal circuit for apheresis. In certain embodiments, such apheresis includes adding a replacement fluid to the blood. The replacement fluid can be fresh frozen plasma (FFP) and / or a predetermined percentage of albumin solution and / or saline. Heparin and / or saline can be added to the replacement fluid depending on the needs of the patient. Saline and / or heparin can be added to the treatment before and / or during the treatment. However, saline and heparin need not be added to the system or can be added via the peripheral venous vasculature. In one embodiment, saline can be added and used for hydration, as will be appreciated by those skilled in the art, in an amount suitable for industry standard therapy. In one embodiment, the patient is administered heparin according to standard anticoagulation during vascular and plasma exchange procedures. Hypocalcemia due to citrate anticoagulants is a common mild adverse event of therapeutic apheresis, but sodium citrate is widely accepted because it can be better handled in healthy donors. Heparin is more appropriate for more diseased populations. By using heparin, the static state of calcium ion activity is maintained. Citrate anticoagulants bind calcium ions. Decrease in calcium ions can lead to an increase in cardiac adverse events such as arrhythmias. For this reason, heparin has been used safely for many years in cardiac applications. Heparin is the standard treatment for patients undergoing vascular treatment.

  In one embodiment, the replacement fluid in the blood that returns to the patient can include one or more therapeutic agents, such as drugs, immune factors, cells, nanoparticles, and / or vectors. Replacement fluids containing therapeutic agents can increase the delivery of such therapeutic agents. The replacement fluid containing the therapeutic agent can be exchanged in a full amount exchange or any amount less than the full amount. In this therapeutic apheresis system, the time per treatment, the amount exchanged, the exchange rate, and the concentration of the components in the components / substitutions returned will depend, among other things, on the severity and condition of the disease process and the particular therapeutic agent. It is.

  1 and 2 illustrate one embodiment of the present disclosure. In particular, blood is received from the patient's aorta or central artery bifurcation, which is generally indicated at 10 and delivered to and / or via the extracorporeal circuit, generally indicated at 12. Temperature (T), pressure (P), velocity (V), acceleration (A), number and / or type of a given blood cell (BC), heparin (H) level, and / or plasma (PI) level, etc. The predetermined blood characteristic is measured or analyzed at the time of delivery and / or before the blood is sent to the extracorporeal circuit 12. As described above, the replacement fluid (RP) can be added to the blood before or after the blood is delivered to the extracorporeal circuit 12. Pre-determined information about the patient, such as blood pressure, pulses, and / or heart rate, is communicated or provided to the extracorporeal circuit 12, controller 14 therein.

  The blood leaving the extracorporeal circuit 12 is sent back to, for example, the aorta or central artery branch of the patient 10. Temperature (T), pressure (P), velocity (V), acceleration (A), number and / or type of a given blood cell (BC), heparin level (H), and / or plasma level (PI), etc. The predetermined blood characteristic is measured or analyzed during blood delivery from the extracorporeal circuit 12 to the aorta or central artery bifurcation of the patient 10. In the control or monitor panel 14, the algorithm described above is used to control the operation of one or more pumps 16, thereby pulsing the blood as it exits the extracorporeal circuit 12 and returns to the patient. As shown in FIG. 2, various parameters or characteristics (eg, temperature) of blood are monitored or measured over delivery through the extracorporeal circuit 12.

  In one embodiment, to perform the procedure, the catheter can be placed as high as possible in the patient's thoracic vertebra to benefit from neural stimulation of blood supply to the spinal nervous system. Such an arrangement is also above the renal artery and provides the benefit of blood supply to the renal system. The amplitude of the pulsatile flow is directly related to the increased blood flow in the kidney, which results in improved organ function that enhances body function between treatments.

  In one embodiment, the exchange time and amount per treatment depends on the severity and pathology of the immunological process required to affect the immunological niche. This means that the self-perpetuating cycle of these immunological processes in the niche is destroyed before further immune factors can be built. Longer time per procedure may help the body's time catch up with fibrinogen, but may require FFP by increasing the amount exchanged. This procedure can replace more than the standard 1-1.5 capacity if needed.

  Although the numerical ranges and parameters indicating the wide range of the present invention are both approximate, the numerical values shown in the specific examples are shown as accurately as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation calculated in their respective testing measurements.

  The systems and / or devices of the present disclosure may be stand-alone or may be operated separately from any other medical or health care system or device. Alternatively, the systems and / or devices of the present disclosure are operable with one or more hemodialysis, cardiopulmonary bypass, extracorporeal membrane oxygenator (ECMO) and / or aquapheresis.

Therefore, the present invention is very suitable for achieving the above-mentioned objects and advantages and the inherent objects and advantages. Many modifications may be made by those skilled in the art, but such modifications are encompassed within the spirit of the invention, as indicated in part by the appended claims.

Claims (16)

Drawing arterial blood from the patient into the extracorporeal circuit;
Performing apheresis on the blood to remove one or more components from the blood;
Returning the portion of the blood to the patient in a pulsatile flow from the extracorporeal circuit.   The method of claim 1, wherein the extracorporeal circuit comprises one or more of an automated blood cell separator, a pump, a sensor, and a heat exchanger.   The method of claim 1, wherein the pulsatile flow is generated by one or more pumps.   The method of claim 1, wherein the pulsatile flow is generated by a pulse wave from the patient.   The method of claim 1, wherein the portion of blood contains a replacement fluid.   The method of claim 1, wherein the portion of blood contains a replacement fluid comprising a therapeutic agent.   The method of claim 1, wherein the pulsatile flow occurs simultaneously with ventricular contraction.   3. The method of claim 2, wherein the pulsatile flow is initiated by draining from the one or more pumps and occurs concurrently with ventricular contraction.   3. The method of claim 2, wherein the pump is filled with blood from a systemic distal artery and returns the blood to the systemic proximal artery.   A system comprising a pump, an apheresis centrifuge, a pulse detector, and a controller for receiving arterial blood and returning a portion of the blood.   The system of claim 10, further comprising a heat exchanger.   The system of claim 10, wherein the pulse detector is an electrocardiography (EKG) device.   The system of claim 10, wherein the pump is one of a positive displacement pump or a kinetic pump.   The system of claim 10, wherein the pump is one or more of a positive displacement pump, a roller pump, a ventricular pump, a piston pump, a kinetic pump, a centrifugal pump, a magnetic pump, and a forced vortex pump.   The system of claim 10, further comprising an electrical lead. The system of claim 10, further comprising one or more of a pressure sensor, a temperature sensor, and a pulse sensor.